The Clinical Effect and Safety of Dihuang Decoction in Henoch-Schönlein Purpura Compared With Different Traditional Programs: A Network Meta-Analysis

This systematic review aims to evaluate the therapeutic efficacy of Dihuang decoction (DD), anti-inflammatory drugs (AIDs), blood circulation improvement drugs (BCIDs), and conventional therapy (CT) in the management of Henoch-Schönlein purpura (HSP) and to establish their comparative effectiveness rankings. Using the Population, Intervention, Comparison, Outcome, Study (PICOS) design framework, we developed a detailed search strategy. The literature search included databases such as PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, Wanfang Data, Weipu Journal Data, and the Chinese Biomedical Database, covering studies published up to June 2024. We included randomized controlled trials that featured the DD as the experimental intervention, with three remaining treatments as comparators. Our analysis encompassed 63 studies with 5,435 participants, divided into 2,817 in the experimental group and 2,618 in the control group. The network meta-analysis suggested that the DD potentially surpasses AIDs, BCIDs, and CT in the management of HSP. This conclusion is supported by its superior SUCRA (Surface Under the Cumulative Ranking) scores across various measures, including the overall effective rate of medication, time to relief or disappearance of the rash, incidence of adverse reactions, time to relief or disappearance of abdominal pain, time to relief or disappearance of arthritic swelling or pain, IgA levels, and the relapse rate within six months (SUCRA scores: 100.0%, 88.3%, 79.8%, 94.4%, 99.9%, 88.3%, and 95.4%, respectively). In terms of overall effectiveness rate, the SUCRA efficacy rankings are as follows: DD > AIDs > AIDs+BCID > BCID > CT. Regarding rash relief and regression time, the SUCRA efficacy rankings are as follows: DD > CT > AIDs+BCID > AIDs. For the incidence rate of adverse reactions, the SUCRA efficacy rankings are as follows: DD > CT > AIDs > BCID > AIDs+BCID. For the relief and disappearance of abdominal pain, the SUCRA efficacy rankings are as follows: DD > CT > AIDs+BCID > AIDs. In terms of relief and disappearance of joint swelling and pain, the SUCRA efficacy rankings are as follows: DD > AIDs+BCID > AIDs. Regarding IgA changes, the SUCRA efficacy rankings are as follows: DD > CT > BCID > AIDs+BCID > AIDs. For the six-month recurrence rate, the SUCRA efficacy rankings are as follows: DD > AIDs > AIDs+BCID > CT. The DD appears to be a more effective alternative for treating HSP compared to AIDs, BCIDs, and CT. We hope that this study will provide better assistance to clinical practice.


Introduction And Background
Henoch-Schönlein purpura (HSP), also known as IgA vasculitis, is an immune complex vasculitis predominantly characterized by IgA deposition in small blood vessels.It primarily presents with skin purpura, joint pain or arthritis, acute enteritis, and glomerulonephritis [1].A study in the field of epidemiology conducted in France revealed that the annual incidence rate of HSP in the general population is estimated to range from 3 to 26.7 cases per 100,000 among children and infants, while it is comparatively lower in adults, ranging from 0.8 to 1.8 cases per 100,000 [2].In an epidemiological survey conducted in China, the male-to-female ratio of patients with the disease was 1.72:1, and the overall incidence showed an increasing trend year by year.Patients were affected in all four seasons, with a higher incidence in the first and fourth quarters (57.84%) and a lower incidence in the second and third quarters (42.16%) [3,4].The complexity of the disease often correlates with specific organ involvement, with renal, pulmonary, or gastrointestinal manifestations being linked to increased morbidity and mortality [5].The recurrent and refractory nature of HSP poses significant clinical challenges.For example, a Chinese study involving 557 patients reported that approximately 61% exhibited gastrointestinal symptoms, ranging from bleeding to severe complications like hematemesis and intestinal obstruction.Pathologically, almost all cases progress to purpuric nephritis, secondary kidney disease of HSP [6].
In Western medicine, the management of HSP predominantly focuses on supportive and symptomatic care [5].This typically involves a combination of medications such as loratadine, hydrocortisone, cimetidine,

Statistical analysis
The NMA was conducted using STATA version 14.0.A network plot provided a succinct summary of the evidence for each intervention.Odds ratios (ORs) for dichotomous variables and mean differences (MD) for continuous variables were used, with 95% confidence interval (CI) calculated and reported.If the ORs do not include 1, or if the mean differences do not include 0, then a P-value of less than 0.05 is considered statistically significant.Global consistency and node-splitting methods were applied to check for inconsistency (P<0.05indicating inconsistency).A comparison-adjusted funnel plot was drawn to assess small study effects.The Surface Under the Cumulative Ranking Curve (SUCRA) was used for intervention ranking, with higher SUCRA values indicating greater efficacy or probability of ranking.Indirect pairwise comparisons among the four interventions were summarized in a league table.

Characteristics of Included Studies
Our NMA evaluated 63 studies [9][10][11], comprising a total of 5,435 participants (Figure 1).All these studies, conducted in China and published up to June 2024, were RCTs.The sample sizes ranged from 30 to 246 patients diagnosed with HSP.The detailed characteristics of these studies are presented in Table 1.

Methodological Quality
The 63 included studies described the generation of random sequences, but none explicitly detailed the plans for concealing the allocation in randomized controlled trials, indicating a potential risk of bias.Two studies were identified as having a potential risk due to incomplete reporting of pre-specified outcome indicators.However, all studies were deemed to have a low risk of bias regarding deviations from intended interventions, missing outcome data, and the measurement of outcomes.The quality and methodological assessments of the included studies are visually summarized in Figure 2, indicating a generally low risk of bias across the literature.

Publication Bias
The funnel plot employs effect size as the horizontal axis and the reciprocal of the standard error of the effect size as the vertical axis, with the axes labeled in their respective natural scales.Each point in the plot represents an included study.Larger sample sizes lead to more reliable results and smaller resulting in smaller standard errors and a concentration of points in the narrow upper region of the funnel plot.Conversely, smaller sample sizes result in larger variance, greater fluctuation, larger standard errors, and the corresponding points dispersed in the wider lower region of the funnel plot, ultimately forming an inverted funnel shape.The funnel plot allows for direct observation of whether effect size estimates from original studies are associated with their sample sizes.When publication bias exists, the funnel plot exhibits asymmetry, indicating a skewed distribution.
Analysis indicates potential publication bias in outcomes related to overall drug efficacy, time to rash relief/disappearance, incidence of adverse reactions, time to abdominal pain relief/disappearance, and time to relief/disappearance of joint swelling and pain.This observation is based on asymmetrical distributions in the funnel plots of these five outcome measures (Figure 18).Such bias could be attributed to the inclusion of numerous studies with small sample sizes.These plots visually represent the potential bias in the respective outcome measures, illustrating a lack of symmetry indicative of publication bias.It is important to note that for IgA levels and the six-month recurrence rate, fewer than 10 studies were included.Therefore, no funnel plots were constructed for these categories.

Discussion
This NMA offers a comprehensive comparison of the efficacy and safety of DD, AIDs, BCIDs, and conventional therapy in managing HSP.The existing body of research in this field is notably deficient, and this study serves to bridge this crucial gap by ranking these treatment methods across various parameters, such as overall drug efficacy, adverse reaction rates, and the time to relief/disappearance of rash, abdominal pain, joint swelling, and pain.It also assesses IgA levels and six-month recurrence rates.Analyzing data from 63 randomized controlled trials, the NMA concludes that DD surpasses other interventions in terms of improving overall medication efficacy and reducing the duration for the relief of rash, abdominal pain, joint swelling, and pain, and lowering adverse reaction rates, IgA levels, and recurrence rates within six months.
The DD is a TCM.Pharmacodynamic studies have shown that dihuang soup has antipyretic, antiinflammatory, antiallergic, antimetabolic, hepatoprotective, microcirculatory, and immune-enhancing, and reduces vascular endothelial cell adhesion molecules in animals [80].Laboratory studies have shown that dihuang soup can effectively inhibit platelet endothelial cell adhesion molecule 1, vascular cell adhesion molecule 1, intercellular adhesion molecule 1, and inducible nitric oxide synthase.Nitric oxide synthase secretion, optimizing blood circulation and improving immune function [30].Xuguang et al. demonstrated that in patients with HSP, pre-treatment sulfate levels were significantly elevated (P<0.05) but reduced after administration of DD (P<0.05).Sulfate maintains cell permeability and regulates intracellular environmental stability.Elevated urinary sulfate concentrations in HSP patients were observed to decrease following treatment, indicating that DD regulates sulfate metabolism in HSP patients [81].Network pharmacological studies have revealed that the positive regulation of nitric oxide biosynthesis, extracellular space, inflammatory response, oxidative stress, cellular response to tumor factors, peroxidase activity, leukocyte adhesion, and information play crucial roles in the treatment of HSP with DD.This suggests that the core targets interact and influence inflammatory response, oxidative stress, and signaling, thereby affecting cellular proliferation, apoptosis, metabolism, and intercellular adhesion.The primary targets of DD in HSP treatment involve the NF-κB pathway, which is involved in vascular inflammatory and immune responses in HSP patients.The activation level of this pathway is disease-related, and DD can alleviate the inflammatory response by inhibiting the NF-κB signaling pathway [14].DD mainly alleviates the symptoms of HSP through its antipyretic, anti-inflammatory, anti-allergic reaction, and microcirculation correction effects [56].
Despite its valuable contributions, this NMA has limitations.The literature included is exclusively in Chinese, which may affect the generalizability of the findings due to variations in study quality.Most studies provide insufficient details on randomization methods, allocation concealment, and blinding procedures, raising concerns about potential bias.Additionally, the limited number of studies for certain outcomes might introduce bias in these specific results.Variability in baseline data across studies, such as patient age, disease duration, and intervention course, may impact the reliability of the NMA outcomes.Furthermore, the lack of direct comparisons between interventions in the NMA's network, due to the absence of a closed loop, could diminish the accuracy of the findings.

Conclusions
In conclusion, while this study supports the efficacy of DD in treating HSP.These research findings indicate that DD could serve as an optimal treatment option for HSP, offering potential guidance for future clinical practice and research.This enables the selection of the most suitable preventive treatment for HSP based on individual patient needs.It also underscores the need for more rigorous research.Future studies should focus on high-quality, large-scale, double-blind randomized controlled trials to further validate and expand upon these NMA results.In addition, future research should delve deeper into the mechanism of action of DD to comprehensively understand how it functions in therapy.Exploring its long-term clinical effects is crucial for assessing its durability and stability throughout treatment.Comparative effectiveness studies with standard therapies are necessary to ensure the rationality and advantages of DD as a treatment option.Furthermore, in-depth investigations into its safety profile are essential to ensure that patients undergoing DD treatment do not experience adverse reactions or complications.
following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work.Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

FIGURE 2 :Figure 3
FIGURE 2: Assessment figure of risk of bias.

FIGURE 3 :
FIGURE 3: Network diagram.(A) Overall effective rate of medication.(B) Time to relief or disappearance of the rash.(C) Incidence of adverse reactions.(D) Time to relief or disappearance of abdominal pain.(E) Time to relief or disappearance of arthritic swelling or pain.(F) IgA levels.(G) Relapse rate within six months.DD: Dihuang Decoction; AIDs: Anti-inflammatory Drugs; BCID: Blood Circulation Improvement Drug; CT: Conventional Therapy.

FIGURE 5 :
FIGURE 5: Cumulative probability line chart of the overall effective rate of medication.DD: Dihuang Decoction; AIDs: Anti-inflammatory Drugs; BCID: Blood Circulation Improvement Drug; CT: Conventional Therapy.

FIGURE 6 :
FIGURE 6: League table of time to relief or disappearance of the rash.DD: Dihuang Decoction; AIDs: Anti-inflammatory Drugs; BCID: Blood Circulation Improvement Drug; CT: Conventional Therapy.

FIGURE 7 :
FIGURE 7: Cumulative probability line chart of time to relief or disappearance of the rash.DD: Dihuang Decoction; AIDs: Anti-inflammatory Drugs; BCID: Blood Circulation Improvement Drug; CT: Conventional Therapy.

FIGURE 10 :
FIGURE 10: League table of time to relief or disappearance of abdominal pain.DD: Dihuang Decoction; AIDs: Anti-inflammatory Drugs; BCID: Blood Circulation Improvement Drug; CT: Conventional Therapy.

FIGURE 11 :
FIGURE 11: Cumulative probability line chart of time to relief or disappearance of abdominal pain.DD: Dihuang Decoction; AIDs: Anti-inflammatory Drugs; BCID: Blood Circulation Improvement Drug; CT: Conventional Therapy.

FIGURE 13 :
FIGURE 13: Cumulative probability line chart of time to relief or disappearance of arthritic swelling or pain.DD: Dihuang Decoction; AIDs: Anti-inflammatory Drugs; BCID: Blood Circulation Improvement Drug; CT: Conventional Therapy.

FIGURE 18 :
FIGURE 18: Funnel plot.(A).Overall effective rate of medication.(B) Time to relief or disappearance of the rash.(C) Incidence of adverse reactions.(D) Time to relief or disappearance of abdominal pain.(E) Time to relief or disappearance of arthritic Note: DD: Dihuang Decoction; AIDs: Anti-Inflammatory Drugs; BCID: Blood Circulation Improvement Drug; CT: Conventional Therapy.

League table of time to relief or disappearance of arthritic swelling or pain.
DD: Dihuang Decoction; AIDs: Anti-inflammatory Drugs; BCID: Blood Circulation Improvement Drug; CT: Conventional Therapy.

League table of relapse rate within six months.
DD: Dihuang Decoction; AIDs: Anti-inflammatory Drugs; BCID: Blood Circulation Improvement Drug; CT: Conventional Therapy.